Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas

Cancer Cell. 2013 Nov 11;24(5):660-72. doi: 10.1016/j.ccr.2013.10.006. Epub 2013 Oct 31.

Abstract

Two recurrent mutations, K27M and G34R/V, within histone variant H3.3 were recently identified in ∼50% of pHGGs. Both mutations define clinically and biologically distinct subgroups of pHGGs. Here, we provide further insight about the dominant-negative effect of K27M mutant H3.3, leading to a global reduction of the repressive histone mark H3K27me3. We demonstrate that this is caused by aberrant recruitment of the PRC2 complex to K27M mutant H3.3 and enzymatic inhibition of the H3K27me3-establishing methyltransferase EZH2. By performing chromatin immunoprecipitation followed by next-generation sequencing and whole-genome bisulfite sequencing in primary pHGGs, we show that reduced H3K27me3 levels and DNA hypomethylation act in concert to activate gene expression in K27M mutant pHGGs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain Neoplasms / genetics*
  • Brain Neoplasms / metabolism
  • Brain Stem Neoplasms / genetics*
  • Brain Stem Neoplasms / metabolism
  • Cell Line, Tumor
  • Child
  • DNA Methylation*
  • Epigenesis, Genetic
  • Gene Expression Regulation, Neoplastic*
  • Genes, Dominant
  • Glioblastoma / genetics*
  • Glioblastoma / metabolism
  • Histone-Lysine N-Methyltransferase / metabolism
  • Histones / genetics*
  • Histones / metabolism
  • Humans
  • Methylation
  • Molecular Sequence Data
  • Mutation, Missense
  • Polycomb Repressive Complex 2 / metabolism
  • Protein Binding
  • Protein Processing, Post-Translational
  • Transcription, Genetic

Substances

  • Histones
  • SUZ12 protein, human
  • Histone-Lysine N-Methyltransferase
  • Polycomb Repressive Complex 2

Associated data

  • GENBANK/GSE34824
  • GENBANK/GSE36245
  • GENBANK/GSE49822